iScience最新文献

Abrupt the aggregation of islet amyloid polypeptide (IAPP), a 37 amino acid hormone, is an expected molecular cause of type 2 diabetes (T2D), a severe pathology that affects more than 30 million Americans. During the past decade, a significant increase in T2D was observed in children, teens, and young adults. Although this increase is associated with changes in nutrition and lifestyle, its origin remains unclear. Our results indicate that fatty acids often used as food supplements drastically accelerate IAPP aggregation and increase the cytotoxicity of IAPP aggregates. Using C. elegans that overexpress IAPP as a model system, we show that an increase in the amount of fatty acids in nematode diets drastically shortens their lifespan. These results indicate that fatty acids present in the diet can accelerate the onset and progression of T2D.

Breast cancer resistance protein (ABCG2) significantly contributes to decreased sensitivity of tumor cells to chemotherapy. While ABCG2 inhibitors exist, multidrug resistance remains unresolved due to limited specificity, toxicity, and heterogeneous expression. To overcome this, we sought to identify key upstream regulators. We assessed drug sensitivity and identified ABCG2 as broadly overexpressed across tumor types and negatively correlated with chemosensitivity. Cell lines with higher ABCG2 expression exhibited lower sensitivity to mitoxantrone, topotecan, and doxorubicin and diminished cytotoxic response. Notably, p38 activation strongly correlated with ABCG2-mediated chemoresistance. Inhibiting p38 phosphorylation effectively downregulated ABCG2 expression and oligomerization. This suppression impaired the drug efflux function of ABCG2, significantly enhancing the cytotoxicity of the chemotherapeutics. Mechanistically, p38 regulated the expression and membrane localization of oligomeric ABCG2, essential for its efflux activity. This study highlights p38 as a promising target to overcome ABCG2-mediated multidrug resistance and improve treatment outcomes for drug-resistant tumors.

Manual lifting tasks pose the risk of musculoskeletal injury, including damage to lumbar intervertebral discs. To assess the risk, spinal joint reaction forces are often estimated using musculoskeletal simulations. However, such analyses require information of external hand force and moment (EHF&M), which has mostly been estimated using simplified models without sufficient validation. This study evaluates the validity of two common EHF&M models by comparing their analysis outcomes to those resulting from directly measured EHF&M. Simplified models yielded negligible errors during the middle phase of symmetric lifting and lowering but caused substantial errors at the beginning and end of each task, leading to inaccurate estimation of peak spinal joint reaction forces. These findings highlight the limitations of simplified models in evaluating mechanical factors of injury risk. The measurement platform and analysis method developed in this study can also contribute to validating EHF&M modeling for other tasks and improving assessment accuracy.

Mammalian visual systems are comprised of multiple brain areas with distinct functional roles. While functional specializations have been proposed in the mouse based on visual feature encoding, the extent to which these specializations are contingent on ongoing behavior is unknown. To address this, we analyzed the neural encoding of visual motion stimuli by thousands of neurons recorded in six cortical and two thalamic visual areas while mice were stationary or locomoting. We found locomotion selectively enhanced visual speed encoding in medial higher visual cortical areas, indicating that these areas may be specialized for processing visual motion during locomotion. By contrast, the encoding of drifting gratings direction was enhanced non-selectively across the mouse visual cortex during locomotion. Our results reveal how a complex interplay of sensory input and ongoing behavior differentially shapes the efficacy of sensory processing in mouse higher visual areas, supporting context-dependent functional roles.

Endothelial cell (EC) injury plays a critical part in the occurrence and progression of renal ischemia-reperfusion injury (IRI). PGC-1α, as a master regulator of mitochondrial function, has been identified as a potential therapeutic target for treating injured ECs. Here, fucoidan-plasmid PGC-1α-gas vesicles (Fuc-pPGC-1α-GVs) are synthesized to identify damaged renal ECs at the early stage of renal IRI through the high affinity of fucoidan to P-selectin, and significantly enhance gene transfection efficiency by ultrasound-mediated controlled cavitation, resulting in the specific overexpression of PGC-1α in injured renal ECs. In vitro and in vivo evidence reveal that ultrasound-mediated gene transfection with Fuc-pPGC-1α-GVs could ameliorate renal IRI by rescuing the function of ECs, decreasing immune cell infiltration, and alleviating renal tubular injury. Mechanistically, overexpressed PGC-1α in injured renal ECs promotes mitophagy and inhibits ROS production by upregulating BNIP3, BNIP3L, and SOD2. This study provides a promising strategy for the early and efficient treatment of renal IRI.